Basal Forebrain Cholinergic Neurons: Linking Down Syndrome and Alzheimer’s Disease

Abstract

Down syndrome (DS, trisomy 21) is characterized by intellectual impairment at birth and Alzheimer’s disease (AD) pathology in middle age. As individuals with DS age, their cognitive functions decline as they develop AD pathology. The susceptibility to degeneration of a subset of neurons, known as basal forebrain cholinergic neurons (BFCNs), in DS and AD is a critical link between cognitive impairment and neurodegeneration in both disorders. BFCNs are the primary source of cholinergic innervation to the cerebral cortex and hippocampus, as well as the amygdala. They play a critical role in the processing of information related to cognitive function and are directly engaged in regulating circuits of attention and memory throughout the lifespan. Given the importance of BFCNs in attention and memory, it is not surprising that these neurons contribute to dysfunctional neuronal circuitry in DS and are vulnerable in adults with DS and AD, where their degeneration leads to memory loss and disturbance in language. BFCNs are thus a relevant cell target for therapeutics for both DS and AD but, despite some success, efforts in this area have waned. There are gaps in our knowledge of BFCN vulnerability that preclude our ability to effectively design interventions. Here, we review the role of BFCN function and degeneration in AD and DS and identify under-studied aspects of BFCN biology. The current gaps in BFCN relevant imaging studies, therapeutics, and human models limit our insight into the mechanistic vulnerability of BFCNs in individuals with DS and AD.

Temporal and brain region‐specific elevations of soluble Amyloid‐β40‐42 in the Ts65Dn mouse model of Down syndrome and Alzheimer’s disease

“…By 40 years of age, nearly all DS patients develop the hallmark neuropathologies of Alzheimer's disease (AD), including extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated tau (Head et al, 2012; Snyder et al, 2020). Notably, some estimates suggest that 90% of DS patients will go on to develop dementia by age 70 (Martinez et al, 2021). AD pathology in DS may be due in part to the increased production of the amyloid precursor protein (APP) and other proteins implicated in AD that lie within the region of HSA21 known as the DS critical region (DSCR).…”

“…Additionally, various brain regions which show distinct abnormalities at different ages in Ts65Dn mice remain to be examined in relation to soluble Aβ 40‐42 accumulation. For example, trisomic mice develop adult‐onset degeneration of basal forebrain cholinergic neurons (BFCNs) as early as 6 months of age (Granholm et al, 2000; Millan Sanchez et al, 2012), which recapitulates the very early alterations in this region seen in both AD and DS (Martinez et al, 2021). The triplication of APP and other surrounding genes in murine chromosome 16 is necessary to induce the early endosomal abnormalities seen at the start of BFCN degeneration in Ts65Dn mice (Cataldo et al, 2003; Millan Sanchez et al, 2012).…”

Biochemical Discrimination of the Down Syndrome-Related Metabolic and Oxidative/Nitrosative Stress Alterations from the Physiologic Age-Related Changes through the Targeted Metabolomic Analysis of Serum

“…In turn, these phenomena should be responsible either for the increased rate of the catabolic pathway of purine degradation [ 41 ], causing higher levels in their serum concentrations [ 42 ], or for the increased rate of glycolysis to compensate the decrease in mitochondrially produced ATP [ 43 , 44 ], causing higher levels in serum lactate [ 45 , 46 ]. The relevant finding is that, since these biochemical dysfunctions worsened by the increasing age of DS patients, they may significantly contribute to the accelerated aging process, with the deterioration of mental status that is characteristic of DS [ 47 , 48 ].…”

“…Previous studies reported anomalies of various amino acids in the serum samples of DS patients, compared to those that were measured in non-DS patients [ 19 , 38 , 39 , 40 ]. Again, in none of these studies was the accelerated aging process characterizing DS patients considered [ 47 , 48 , 67 ], so that the comparisons were performed between groups of non-DS and DS patients that were matched for sex and, most importantly, age.…”

Effects of transcranial magnetic stimulation on neurobiological changes in Alzheimer's disease (Review)

“…These changes in NTFs in AD are critical for neurodegenerative processes. Studies have observed that cognitive decline and the underlying pathologies of AD are associated with neurodegeneration in various regions of the brain, especially cholinergic neurons of the basal forebrain and their projections for the hippocampus and cortex ( 72 , 75 , 76 ). It has been suggested that the loss of NTFs may be a mechanism involved in the pathogenesis of AD ( 77 ).…”